Anemarrhena asphodeloides-derived small extracellular vesicle ameliorate diabetes-induced muscle atrophy via activating Pink1-mediated mitophagy.

BACKGROUND

Diabetes-induced muscle atrophy, characterized by progressive loss of skeletal muscle mass and function, poses a major challenge in diabetes management. To address this, we developed a phyto-exosomal formulation derived from Anemarrhena asphodeloides small extracellular vesicle (AA-sEV) and evaluated its therapeutic potential against diabetic muscle atrophy.

METHODS

AA-sEV were isolated by ultracentrifugation and characterized for exosomal morphology. The therapeutic efficacy of AA-sEV was assessed through in vivo studies in diabetic db/db mice and in vitro assays using C2C12 myoblasts exposed to high glucose conditions.

RESULTS

Fluorescently labeled AA-sEV efficiently accumulated in skeletal muscle tissue and myoblasts. Oral administration of AA-sEV enhanced muscle performance, as indicated by increased grip strength and hanging endurance, restoration of myofiber cross-sectional area, and upregulation of FNDC5 expression. Transcriptomic analysis revealed that mitophagy served as the central mechanism mediating AA-sEV's therapeutic effects. Specifically, AA-sEV activated the Pink1/Parkin-dependent mitophagy pathway, reducing mitochondrial reactive oxygen species accumulation. This restoration of mitochondrial quality control promoted the MyoG/MyoD1-driven anabolic program while suppressing the MuRF1/MAFbx-mediated catabolic response. Treatment with the mitophagy inhibitor 3-methyladenine abolished the anabolic and catabolic regulatory effects of AA-sEV under hyperglycemic conditions.

CONCLUSIONS

Our findings demonstrate that AA-sEV mitigate diabetes-induced muscle atrophy by restoring protein anabolic-catabolic balance via Pink1-mediated mitophagy. These results highlight a novel extracellular vesicle-based therapeutic strategy for managing diabetic myopathy and related complications.